EP0955299B1 - Nouveaux dérivés benzothiophéniques, benzofuraniques et indoliques, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent - Google Patents

Nouveaux dérivés benzothiophéniques, benzofuraniques et indoliques, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent Download PDF

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EP0955299B1
EP0955299B1 EP99401010A EP99401010A EP0955299B1 EP 0955299 B1 EP0955299 B1 EP 0955299B1 EP 99401010 A EP99401010 A EP 99401010A EP 99401010 A EP99401010 A EP 99401010A EP 0955299 B1 EP0955299 B1 EP 0955299B1
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formula
group
branched
linear
compounds
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EP0955299A1 (fr
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Guillaume De Nanteuil
Christine Lila
Tony Verbeuren
Alain Rupin
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Laboratoires Servier SAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/64—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to new benzothiophenic, benzofuranic and indole, their preparation process and the pharmaceutical compositions containing them. These new compounds are useful for their therapeutic activity in the field of fibrinolysis and thrombosis, thanks to their property inhibiting the activity of PAI-1.
  • PAI-1 is a potent inhibitor of plasminogen activators (tissue activator of plasminogen and urokinase). It causes, in-vitro and in-vivo, the inhibition of clot lysis fibrinous formed by the action of thrombin on fibrinogen. Many studies have shown that in humans, high levels of PAI-1 are associated with more frequent occurrence of thromboembolic diseases. In addition, in models thrombosis and thrombolysis tests, inhibition of PAI-1 activity by anti-PAI-1 monoclonal antibodies decrease the incidence of thrombosis or reocclusion.
  • the therapeutic value of molecules having the property of inhibiting the activity of PAI-1 within the fibrin clot formed or in formation is therefore to allow its early lysis before its complexation with factor XIIIa and thus reduce the incidence of accidents thromboembolism in patients with elevated PAI-1 levels.
  • Such compounds are of therapeutic interest in all pathologies whose origin is thrombosis (such as myocardial infarction, angina, intermittent claudication, stroke cerebral, deep vein thrombosis, or pulmonary embolism) as well as for conditions in which the thrombotic risks are increased (such as hypertension, high cholesterol, diabetes, obesity, genetic clotting abnormalities (factor V leiden, protein C and S deficiency) or acquired coagulation abnormalities).
  • the compounds of the present invention in addition to being new, have been found to be PAI-1 inhibitors more potent than those described in the literature, which therefore makes them potentially useful for the treatment of thrombosis, or pathologies whose origin is thrombosis...
  • acids hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methane sulfonic, camphoric, etc ...
  • aryl group is intended to mean a phenyl, naphthyl, tetrahydronaphthyl or dihydronaphthyl group, each of these groups being optionally substituted identically or differently, by one or more halogen atoms, hydroxy, cyano, nitro or C 1 alkyl groups -C 6 ) linear or branched, trihaloalkyl (C 1 -C 6 ) linear or branched, alkoxy (C 1 -C 6 ) linear or branched, acyl (C 1 -C 6 ) linear or branched, carboxy, alkoxycarbonyl (C 1 -C 6 ) linear or branched, amino (optionally substituted by one or two groups, identical or different, (C 1 -C 6 ) linear or branched alkyl).
  • cycloalkyl group is meant a mono or bicyclic group, comprising from 3 to 8 carbon atoms.
  • heterocycle is meant a mono or bicyclic group, saturated or unsaturated, of aromatic or non-aromatic nature, of 5 to 12 chains containing one, two or three heteroatoms, identical or different, chosen from oxygen, nitrogen or sulfur, it being understood that the heterocycle can be optionally substituted, in an identical or different manner, by one or more halogen atoms, hydroxy groups, linear or branched (C 1 -C 6 ) alkyl, linear or branched (C 1 -C 6 ) trihaloalkyl, linear or branched (C 1 -C 6 ) alkoxy, aryloxy, linear or branched (C 1 -C 6 ) arylalkoxy, amino (optionally substituted by one or two linear or branched (C 1 -C 6 ) alkyl groups), acyl ( C 1 -C 6 ) linear or branched, alkoxycarbonyl (C 1 -C 6 ) linear or branched, nitro, oxo.
  • heteroaryl a heterocycle, optionally substituted, mono or bicyclic unsaturated, at least one of the rings of which has an aromatic character.
  • heteroaryls such as pyridine, pyrimidine, quinoline, isoquinoline, 1,3-dihydro-2 H -pyrrolopyridine-2-one, 3 H -imidazopyridine, 1 H -pyrrolopyridine, 1,2,3, 4-tetrahydronaphtpyridine or 2,3-dihydro-1 H -pyrrolopyridine.
  • the preferred compounds of the invention are those for which X represents a sulfur atom or an NR 3 group with R 3 as defined in formula (I).
  • the preferred compounds of the invention are those for which Y represents an oxygen atom.
  • the substituents R 1 preferred according to the invention are the groups chosen from phenyl optionally substituted with a group as defined in formula (I), optionally substituted quinolyl, and optionally substituted pyridinyl.
  • the preferred substituents R 2 according to the invention are the groups chosen from aryl and heterocycle, each of these groups being optionally substituted. According to an advantageous variant, the preferred substituent R 2 is the pyridinyl group.
  • the preferred compounds are those for which X represents a sulfur atom and Y represents an oxygen atom.
  • the compounds of formula (II) are obtained according to conventional methods of organic synthesis.
  • the compounds of formula (II) in which X represents an oxygen atom and Q a hydroxy group are obtained from compounds of formula (II / A): whose synthesis scheme is described in J. Med.
  • Ra, Rb, Rc, Rd have the same definitions as in formula (I) and R ′ represents a linear or branched (C 1 -C 6 ) alkyl group, and the hydroxy function of which is protected, in basic condition, by a trialkylsilyl group, then the ester function of which is reduced in primary alcohol function by the action of LiAlH 4 for example, the latter then being oxidized to the aldehyde function, then from which the alcohol function under the action of nBu 4 NF, making it possible to obtain the particular compounds of formula (II) in which X represents an oxygen atom and Q represents a hydroxy group.
  • the compounds of formula (III), (IV), (VII), (VIII), (XI), (XIII) and (XIV) are either compounds commercial, or obtained according to conventional organic synthesis methods.
  • the present invention also relates to pharmaceutical compositions containing as active principle at least one compound of formula (I), its optical isomers or one of its salts of addition to a pharmaceutically acceptable base or acid, alone or in combination with one or more non-toxic, pharmaceutically acceptable inert excipients or vehicles.
  • compositions according to the invention particular mention will be made of those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous) administration, per or transcutaneous, nasal, rectal, perlingual, ocular or respiratory, and in particular single or coated tablets, sublingual tablets, sachets, capsules, tablets, suppositories, creams, ointments, dermal gels, preparations injectable or drinkable, aerosols, eye or nasal drops, etc ...
  • the useful dosage varies according to the age and weight of the patient, the route of administration, the nature and the severity of the disorder and the taking of any associated treatments and ranges from 0.1 mg to 1 g in one or more doses per day.
  • the starting materials used are known products or prepared according to procedures known.
  • a solution containing 6 mmol of the product obtained in Stage E, 30 mmol of ethyl 4-pyridylacetate and 5 ml of acetic anhydride is brought to 100 ° C for 18 hours. After returning to ambient temperature, the reaction is hydrolyzed with a saturated NaHCO 3 solution, extracted with ethyl acetate. The organic phases are then washed with water, then with an NaCl solution, dried over calcium sulphate, filtered and concentrated under reduced pressure. Chromatography on silica gel (dichloromethane / ethanol: 98/2) allows the expected product to be isolated. Melting point : 164 ° C
  • Example 6 The compound obtained in Example 6 after stage F is used as substrate, which is treated with a stream of hydrogen in the presence of Pd / C at 10% in methanol, for 24 hours. Filtration, at the end of the reaction, followed by chromatography on silica gel allows the expected product to be isolated.
  • reaction medium is hydrolyzed by addition of 100 ml of a 1N HCl solution, then extracted with ethyl acetate; the combined organic phases are washed with water, then with a saturated NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. Chromatography on silica gel (Pentane / Ethyl acetate: 90/10) allows 2.78 g of the expected product to be isolated. Melting point : 110 ° C
  • Example 2 The procedure is as in Example 2, using the product obtained in Example 9 as a substrate.
  • Example 3 The procedure is as in Example 3, using the product obtained in Example 10 as the substrate.
  • Example 2 The procedure is as in Example 2, then as in Example 3, using the product obtained in Example 12 as the substrate.
  • a solution containing 6.5 mmol of the compound obtained in stage H, in 16 ml of dimethylformamide, 1.5 equivalents of N-phenylglycine ethyl ester and 1.5 equivalents of K 2 CO 3 is brought to 80 ° C for 18 hours .
  • the residue is diluted with ethyl acetate and the organic phase is washed with water, then with a saturated NaCl solution, dried over calcium sulphate, filtered and evaporated under reduced pressure.
  • Chromatography on silica gel (Toluene / Ethyl acetate: 98/2) allows 2.56 g of the expected product to be isolated in the form of an oil.
  • Example 3 The procedure is as in Example 3, using the compound obtained in Example 15 as the substrate.
  • Example 14 The procedure is as in Example 14, using in Stage I, as reagent, the N-benzylglycine ethyl ester, then as in Example 15.
  • Example 16 The procedure is as in Example 16, using the product obtained in Example 17 as a substrate.
  • a solution containing 41 mmol of the compound obtained in stage H of Example 14 and 78 mmol sodium azide in 80 ml of dimethylformamide is stirred at room temperature for 48 hours.
  • the reaction medium is then concentrated under reduced pressure.
  • the residue is diluted with ethyl acetate, washed with water and then with a saturated NaCl solution.
  • the sentence organic is then dried over calcium sulphate, filtered and evaporated, making it possible to obtain 15.4 g of the expected product in the form of an oil.
  • EXAMPLE 28 2 - [( ⁇ [5,6-Dimethoxy-3- (4-methoxyphenoxy) benzo [ b ] thiophene-2-yl] methyl ⁇ amino) sulfonyl] ethyl acetate
  • Example 3 The procedure is as in Example 3, replacing the water with ethanol, and using the compound obtained in Example 28 as a substrate.
  • EXAMPLE 30 Ethyl 3- [5,6-Dimethoxy-3- (4-methoxyphenoxy) benzo [ b ] thiophene-2-yl] -2- (4-pyridyl) -2-propanoate
  • Example 2 The procedure is as in Example 2 then in Example 3, using the product as a substrate from example 30.
  • Example 2 The procedure is as in Example 1, using Stage E, as reagent, 3-pentylphenol, then the procedure of Example 2 and Example 3 is followed.
  • Example 2 The procedure is as in Example 1, using as starting material in stage A, the acid 3-chloro-2,5-dimethoxycynnamique, then the protocol described in Example 2 is followed.
  • Example 2 The procedure is as in Example 1, using as starting material in stage A, the acid 4,5-dichlorocinnamique, then the protocol described in Example 2 is followed.
  • Example 2 The procedure is as in Example 1, using 2,4-difluorophenol as the reagent in Stage E, then we follow the protocol described in Example 2.
  • Example 2 The procedure is as in Example 1, using as reagent in stage E, 3-hydroxypyridine, then we follow the protocol described in Example 2.
  • Example 2 The procedure is as in Example 1, using as reagent in stage E, 4-methoxybenzenethiol, then we follow the protocol described in Example 2.
  • Example 3 The procedure is as in Example 3, using the product of Example 33 as the substrate. Melting point :> 260 ° C
  • Example 3 The procedure is as in Example 3, using the product of Example 35 as a substrate. Fusion product : > 260 ° C
  • Example 3 The procedure is as in Example 3, using the product of Example 37 as the substrate.
  • Example 1 The procedure is as in Example 1, using 4-chlorophenol as a reagent in Stage E, then the protocol described in Example 2 and then Example 3 is followed.
  • Example 2 The procedure is as in Example 1, using methyl 4-hydroxy benzoate as stage E reagent, then the protocol described in Example 2 and then Example 3 is followed.
  • Example 3 The procedure is as in Example 3, using the product of Example 36 as the substrate.
  • Example 3 The procedure is as in Example 3, using the product of Example 38 as the substrate.
  • Example 2 The procedure is as in Example 1, using as reagent in Stage E 3-methoxy-phenol, then the protocol described in Example 2 is followed, then Example 3.
  • Example 3 Elementary microanalysis: VS% H% NOT% S% calculated 61.85 4.15 2.89 6.60 find 61.66 4.21 2.89 6.36
  • Example 3 The procedure is as in Example 1, using as reagent in Stage E 4-trifluoromethyl-phenol, then the protocol described in Example 2 is followed, then Example 3.
  • Example 3 The procedure is as in Example 1, using ethyl 4-hydroxyphenylethanoate as stage E reagent, then the protocol described in Example 2 is followed, then Example 3.
  • Example 1 The procedure is as in Example 1, using as reagent in Stage E, 4- (trifluoromethoxy) phenol, then the protocol described in Example 2 is followed, then Example 3.
  • Example 3 Elementary microanalysis: VS% H% NOT% S% calculated 55.66 3.18 2.60 5.94 find 56.07 3.00 2.64 6.04
  • stage A 3,4-bis (benzyloxy) cinnamic acid and as stage E reagent 4- (pyridinyl-4-oxy) phenol.
  • Example 2 The procedure is as in Example 1, using as substrate in stage A 3,4-bis (benzyloxy) cinnamic acid as reagent in stage E, 2-methyl-5-hydroxy-pyridine, then the protocol is followed. described in Example 2. Melting point : 228 ° C
  • Example 2 The procedure is as in Example 1, using as substrate at stage A 4-benzyloxy-3-methoxy-cinnamic acid and as reactant at stage E 4- (benzyloxy) phenol, then the protocol described in l 'example 2. Melting point : 216 ° C
  • Example 1 The procedure is as in Example 1 using as substrate in stage A 3,4-bis (benzyloxy) cinnamic acid and as reactant in stage E 4- (1 H -imidazol-1-yl) phenol, then follows the protocol described in Example 2 then Example 3.
  • Example 2 The procedure is as in Example 1, using as substrate at stage A, 3,4-bis (benzyloxy) cinnamic acid and as reagent at stage E, 6-methoxy-3-pyridinol, then the protocol is followed. described in Example 2. Melting point : 188 ° C
  • Example 2 The procedure is as in Example 1, using as reagent in stage E 1,4-dihydroxy-2-oxo-1,2-dihydro-pyridine, then we follow the protocol described in Example 2.
  • Example 2 The procedure is as in Example 1, using 5-hydroxy-1 H -benzimidazol as the reagent in Stage E, then the protocol of Example 2 is followed.
  • Example 2 The procedure is as in Example 1, using 5-hydroxy-1 H -indole as reactant in Stage E, then the protocol of Example 2 is followed.
  • the inhibition of PAI-1 activity was carried out in vitro in microplate wells in which the formation and then the lysis of a fibrin clot is continuously monitored in turbidimetry using a spectrophotometer. To do this, using as diluent a 50 mM phosphate buffer pH 7.4 containing 0.05% bovine serum albumin, 50 ⁇ l of the inhibitor is brought into contact with 50 ⁇ l of a solution of active PAI-1 recombinant. human at 2 nM for 5 minutes at room temperature.
  • the concentration of the product inhibiting 50% of the activity of PAI-1 is sought by measuring the absorbance of the clot two hours after fibrinoformation in the presence of PAI-1 and of increasing concentration of the product.
  • the IC 50 values of the compounds of the invention as well as that of the reference substance, XR 5082, are presented in Table 1. The results demonstrate the superior fibrinolytic activity of the compounds of the invention. Fibrinolytic activity of the compounds of the invention Example IC50 ( ⁇ M) 43 13 44 7 66 2.2 67 5 XR 5082 190
  • Preparation formula for 1000 tablets dosed at 10 mg Composed of the example 10 g hydroxypropyl 2 g polyvinylpyrrolidone 2 g Wheat starch 10 g Lactose 100g Magnesium stearate 3 g

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  • Organic Chemistry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
EP99401010A 1998-04-27 1999-04-26 Nouveaux dérivés benzothiophéniques, benzofuraniques et indoliques, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent Expired - Lifetime EP0955299B1 (fr)

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FR9805239 1998-04-27
FR9805239A FR2777886B1 (fr) 1998-04-27 1998-04-27 Nouveaux derives benzothiopheniques, benzofuraniques et indoliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

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EP0955299A1 EP0955299A1 (fr) 1999-11-10
EP0955299B1 true EP0955299B1 (fr) 2002-03-13

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US (1) US6048875A (da)
EP (1) EP0955299B1 (da)
JP (1) JP3957424B2 (da)
CN (1) CN1211362C (da)
AT (1) ATE214387T1 (da)
AU (1) AU744456B2 (da)
BR (1) BR9901298A (da)
CA (1) CA2270086C (da)
DE (1) DE69901006T2 (da)
DK (1) DK0955299T3 (da)
ES (1) ES2174579T3 (da)
FR (1) FR2777886B1 (da)
HK (1) HK1022694A1 (da)
HU (1) HUP9901403A1 (da)
NO (1) NO319101B1 (da)
NZ (1) NZ335388A (da)
PT (1) PT955299E (da)
ZA (1) ZA992941B (da)

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US6162930A (en) 1998-03-06 2000-12-19 Baylor University Anti-mitotic agents which inhibit tubulin polymerization
FR2799756B1 (fr) * 1999-10-15 2001-12-14 Adir Nouveaux derives benzothiopheniques, benzofuraniques et indoliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
WO2001068654A2 (en) * 2000-03-10 2001-09-20 Baylor University Tubulin binding ligands and corresponding prodrug constructs
CA2445712A1 (en) * 2001-05-31 2002-12-05 Cellegy Pharmaceuticals, Inc. Store operated calcium influx inhibitors and methods of use
TWI224101B (en) 2001-06-20 2004-11-21 Wyeth Corp Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
DK1397130T3 (da) * 2001-06-20 2007-11-12 Wyeth Corp Substituerede indolsyrederivater som inhibitorer af plasminogenaktivatorinhibitor-1 (PAI-1)
UA80453C2 (en) * 2002-12-10 2007-09-25 Derivatives of substituted dyhydropyranoindol-3,4-dion as inhibitors of plasminogen activator inhibitor-1 (pai-1)
AU2003296324A1 (en) 2002-12-10 2004-06-30 Wyeth Aryl, aryloxy, and alkyloxy substituted 1h-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1)
CN1723197A (zh) * 2002-12-10 2006-01-18 惠氏公司 作为纤溶酶原激活物抑制剂－1(pai－1)的抑制剂的取代3－烷基和3－芳基烷基1h－吲哚－1－基乙酸衍生物
AU2003296323A1 (en) * 2002-12-10 2004-06-30 Wyeth Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1)
DE60306548T2 (de) * 2002-12-10 2007-06-21 Wyeth Substituierte 3-carbonyl-1-yl-essigsäure-derivate als plasminogen aktivator inhibitor(pai-1) inhibitoren
US7265148B2 (en) 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7332521B2 (en) 2003-09-25 2008-02-19 Wyeth Substituted indoles
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US7141592B2 (en) 2003-09-25 2006-11-28 Wyeth Substituted oxadiazolidinediones
US7420083B2 (en) 2003-09-25 2008-09-02 Wyeth Substituted aryloximes
US7342039B2 (en) 2003-09-25 2008-03-11 Wyeth Substituted indole oximes
US7411083B2 (en) 2003-09-25 2008-08-12 Wyeth Substituted acetic acid derivatives
US7442805B2 (en) * 2003-09-25 2008-10-28 Wyeth Substituted sulfonamide-indoles
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DK0955299T3 (da) 2002-06-24
CN1235156A (zh) 1999-11-17
HU9901403D0 (en) 1999-06-28
HK1022694A1 (en) 2000-08-18
AU2402199A (en) 1999-11-04
DE69901006D1 (de) 2002-04-18
EP0955299A1 (fr) 1999-11-10
NO991957L (no) 1999-10-28
AU744456B2 (en) 2002-02-21
ES2174579T3 (es) 2002-11-01
BR9901298A (pt) 2000-05-02
JP3957424B2 (ja) 2007-08-15
ATE214387T1 (de) 2002-03-15
CN1211362C (zh) 2005-07-20
HUP9901403A1 (hu) 2000-06-28
FR2777886A1 (fr) 1999-10-29
FR2777886B1 (fr) 2002-05-31
CA2270086C (fr) 2005-04-05
PT955299E (pt) 2002-07-31
DE69901006T2 (de) 2002-11-07
ZA992941B (en) 1999-10-26
JPH11349586A (ja) 1999-12-21
NO319101B1 (no) 2005-06-20
US6048875A (en) 2000-04-11
NZ335388A (en) 2000-03-27
NO991957D0 (no) 1999-04-23
CA2270086A1 (fr) 1999-10-27

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